Systemic lupus erythematosus (SLE) is a complex, partially understood autoimmune disease that affects 300,000 Americans. In African-American women, SLE has been estimated to occur as frequently as 1 in every 250. African-Americans have a higher incidence and prevalence of lupus by about 3.5-fold compared to European-derived peoples. Understanding the mechanisms of lupus is imperative if we have any hope of finding therapies that will safely treat this disease. We cannot fully understand lupus without explaining its genetic architecture. Genes that alter risk are origins of disease causation and must be involved in disease pathogenesis. Many strategies are now available to discover these genes. Candidate gene approaches have given way to reverse genetics and the possibility of evaluating the entire genome has very recently undergone a technical scientific revolution providing the capacity to evaluate over 1 million markers per individual subject. In Project 2, we will evaluate the genomics of lupus in African-Americans by exploiting the new technologies and applying a genome-wide association scan in 1,400 cases and 400 controls on the Affymetrix 6.0 array. We will also have genotype data from an additional 1,000 African-American out-of-study controls already typed on the Affymetrix 6.0 array, giving us 80% power to detect odds ratios >1.38 when applying a threshold of p=5xl0E-8. We will further explore powerful hits in a large replication experiment of ~15,000 SNPs in 9,000 subjects of African-American, Hispanic and Asian descent. We will physically define the genomic interval containing the association effect using the trans-racial and fine mapping approaches. We will construct haplotypes and apply standard regression methods to identify and characterize genetic effects. We will use resequencing to identify novel variants. The candidate polymorphisms and their surrogates will be evaluated for genomic mechanism(s). When successfully completed this POI project will provide new genes with fundamental insights into the mechanisms by which lupus is generated. At the same time the infrastructure developed through this POI will provide the basis from which to evaluate compelling candidate genes important for lupus in minority populations. RELEVANCE (See instructions): Systemic lupus erythematosus (SLE) is a debilitating and often life-threatening disease, particulariy in African-Americans. Most progress to date has been in European populations. We have the opportunity with this P01 to better undersand lupus in African-Americans. The knowledge gained will form the basis for understanding the pathogenesis of this disorder, leading to new, safer, and more specific therapeutics.